Crystalline composition of tildacerfont and methods of use and preparation thereof

ABSTRACT

Described herein are crystalline composition, methods of making such crystalline composition, pharmaceutical compositions and medicaments comprising such crystalline composition, and methods of using such crystalline composition in the treatment of conditions, diseases, or disorders that would benefit from modulation of Corticotropin-releasing hormone receptor 1 (CRF1).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/720,074, filed Apr. 13, 2022, which claims the benefit of U.S.Provisional Application No. 63/281,462, filed on Nov. 19, 2021, whichare incorporated herein by reference in their entirety.

BACKGROUND

Corticotropin releasing factor (CRF) is a 41 amino acid peptide that isthe primary physiological regulator of proopiomelanocortin (POMC)derived peptide secretion from the anterior pituitary gland. In additionto its endocrine role at the pituitary gland, immunohistochemicallocalization of CRF has demonstrated that the hormone has a broadextrahypothalamic distribution in the central nervous system andproduces a wide spectrum of autonomic, electrophysiological andbehavioral effects consistent with a neurotransmitter or neuromodulatorrole in the brain. There is also evidence that CRF plays a significantrole in integrating the response in the immune system to physiological,psychological, and immunological stressors.

SUMMARY OF THE INVENTION

In a first aspect, the present disclosure provides a crystallinecomposition according to Formula I:

In some embodiments, the crystals of the crystalline compositionaccording to Formula I have unit cell parameters at T=150° K of:a=34.003(4) Å, b=6.5843(13) Å, c=21.062(5) Å; β=108.703(12°),V=4466.5(15) Å³ and a monoclinic C2/c space group.

In some embodiments, the crystals of the crystalline compositionaccording to Formula I is characterized by:

-   -   (a) an X-ray powder diffraction pattern comprising peaks at        10.84±0.2° 2-θ, 15.96±0.2° 2-θ, 23.44±0.2° 2-θ, and 24.80±0.2°        2-θ, and as measured by X-ray powder diffraction using an X-ray        wavelength of 0.71073 Å;    -   (b) an X-ray powder diffraction pattern substantially the same        as shown in FIG. 1 ;    -   (c) a differential scanning calorimetry (DSC) thermogram        comprising an endotherm in the range of about 160° C. to 170°        C.;    -   (d) a differential scanning calorimetry (DSC) thermogram        comprising an endotherm with an onset of about 164° C. and a        peak of about 166° C.;    -   (e) a differential scanning calorimetry (DSC) thermogram        substantially the same as shown in FIG. 2 ;    -   (f) a thermogravimetric analysis (TGA) thermogram comprising a        loss in mass of about 11% over a temperature range of about        25° C. to about 200° C.;    -   (g) a thermogravimetric analysis (TGA) thermogram substantially        the same as shown in FIG. 3 ; or    -   (h) combinations thereof.

In some embodiments, the crystalline composition according to Formula Iis characterized by an X-ray powder diffraction pattern comprising peaksat 10.84±0.2° 2-θ, 15.96±0.2° 2-θ, 23.44±0.2° 2-θ, and 24.80±0.2° 2-θ,and as measured by X-ray powder diffraction using an X-ray wavelength of0.71073 Å. In some embodiments, the X-ray powder diffraction patternfurther comprising at least one peak selected from 5.44±0.2° 2-θ,20.78±0.2° 2-θ, 22.74±0.2° 2-θ, 23.04±0.2° 2-θ, 26.80±0.2° 2-θ, and28.86±0.2° 2-θ, and as measured by X-ray powder diffraction using anX-ray wavelength of 0.71073 Å. In some embodiments, the X-ray powderdiffraction pattern further comprising at least five peaks selected from8.82±0.2° 2-θ, 11.70±0.2° 2-θ, 14.60±0.2° 2-θ, 15.56±0.2° 2-θ,16.70±0.2° 2-θ, 18.82±0.2° 2-θ, 19.18±0.2° 2-θ, 20.02±0.2° 2-θ,20.50±0.2° 2-θ, 21.72±0.2° 2-θ, 25.52±0.2° 2-θ, 25.92±0.2° 2-θ,26.94±0.2° 2-θ, and 28.00±0.2° 2-θ, and as measured by X-ray powderdiffraction using an X-ray wavelength of 0.71073 Å. In some embodiments,the crystalline composition is characterized by an X-ray powderdiffraction pattern substantially the same as shown in FIG. 1 .

In some embodiments, the crystalline composition is characterized by adifferential scanning calorimetry (DSC) thermogram comprising anendotherm in the range of about 160° C. to 170° C. In some embodiments,the crystalline composition is characterized by a differential scanningcalorimetry (DSC) thermogram comprising an endotherm with an onset ofabout 164° C. and a peak of about 166° C. In some embodiments, thecrystalline composition is characterized by a melting point of about166° C. In some embodiments, the crystalline composition ischaracterized by a differential scanning calorimetry (DSC) thermogramsubstantially the same as shown in FIG. 2 .

In some embodiments, the crystalline composition is characterized by athermogravimetric analysis (TGA) thermogram comprising a loss in mass ofabout 11% over a temperature range of about 25° C. to about 200° C. Insome embodiments, the crystalline composition is characterized by athermogravimetric analysis (TGA) thermogram substantially the same asshown in FIG. 3 .

In some embodiments, the crystalline composition is characterized by adynamic vapor sorption (DVS) trace substantially the same as shown inFIG. 4 .

In a second aspect, the present disclosure provides a pharmaceuticalcomposition comprising crystalline composition according to Formula I:

and at least one pharmaceutically acceptable carrier or excipient.

In a third aspect, the present disclosure provides a method of preparinga crystalline composition according to Formula I:

wherein the method comprises:

-   -   a) dissolving        4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholine        (Compound 1) and oxalic acid in a solvent;    -   (b) heating the solution or slurry from step (a); and    -   (c) crystallizing the solution or slurry obtained in step (b) to        obtain the crystalline composition according to Formula I.

In some embodiments of the method of preparing the crystallinecomposition according to Formula I, the solvent in step (a) comprisesacetone, heptane, water, 2-butanol, ethyl acetate, 2-propanol, methyltert-butyl ether, ethanol, methyl ethyl ketone, 1-pentanol, or acombination thereof. In some embodiments, the solvent in step (a) isheptane. In some embodiments, the solvent in step (a) is methyltert-butyl ether or methyl ethyl ketone. In some embodiments, thesolvent in step (a) is a mixture of heptane and methyl ethyl ketone. Insome embodiments, step (b) is heated at about 50° C.

In another aspect, the present disclosure provides a method of treatingor preventing testicular adrenal rest tumors (TART) or ovarian adrenalrest tumors (OART) in a subject in need thereof, comprisingadministering to the subject a crystalline composition according toFormula I as described herein, or the pharmaceutical compositioncomprising the crystalline composition according to Formula I asdescribed herein. In some embodiments, the subject has congenitaladrenal hyperplasia (CAH).

In another aspect, the present disclosure provides a method of treatingcongenital adrenal hyperplasia (CAH) in a subject in need thereof,comprising administering to the subject a crystalline compositionaccording to Formula I as described herein, or a pharmaceuticalcomposition comprising the crystalline composition according to FormulaI as described herein. In some embodiments, the CAH is a classic CAH. Insome embodiments, the CAH is a non-classical CAH.

In another aspect, the present disclosure provides a method of improvinghyperandrogenic symptoms in a subject in need thereof, comprisingadministering to the subject a crystalline composition according toFormula I as described herein, or the pharmaceutical compositioncomprising the crystalline composition according to Formula I asdescribed herein. In some embodiments, the hyperandrogenic symptoms areselected from the group consisting of acne, hirsutism, and alopecia.

In another aspect, the present disclosure provides a method of treatingmenstrual irregularity, ovulatory dysfunction or infertility, in asubject in need thereof, comprising administering to the subject acrystalline composition according to Formula I as described herein, orthe pharmaceutical composition comprising the crystalline compositionaccording to Formula I as described herein.

In another aspect, the present disclosure provides a method of improvingmetabolic symptoms in a subject in need thereof, comprisingadministering to the subject a crystalline composition according toFormula I as described herein, or the pharmaceutical compositioncomprising the crystalline composition according to Formula I asdescribed herein. In some embodiments, the metabolic symptoms areselected from the group consisting of body weight, BMI, fat mass, waistcircumference, blood pressure and glycemic control.

In another aspect, the present disclosure provides a method of treatingpolycystic ovary syndrome with functional ovarian hyperandrogenism andfunctional adrenal hyperandrogenism (PCOS−FOH+FAH) in a subject in needthereof, comprising administering to the subject a crystallinecomposition according to Formula I as described herein, or thepharmaceutical composition comprising the crystalline compositionaccording to Formula I as described herein.

In another aspect, the present disclosure provides a method of treatingpolycystic ovary syndrome with functional adrenal hyperandrogenism(PCOS-FAH) in a subject in need thereof, comprising administering to thesubject a crystalline composition according to Formula I as describedherein, or the pharmaceutical composition comprising the crystallinecomposition according to Formula I as described herein.

In another aspect, the present disclosure provides a method of treatingendometriosis or improving the symptoms of endometriosis in a subject inneed thereof, comprising administering to the subject a crystallinecomposition according to Formula I as described herein, or thepharmaceutical composition comprising the crystalline compositionaccording to Formula I as described herein. In some embodiments, theadministration of the crystalline composition or the pharmaceuticalcomposition improves the symptom of pain experienced by the subject. Insome embodiments, the administration of the crystalline composition orthe pharmaceutical composition reduces the symptoms of pain experiencedby the subject. In some embodiments, the administration of thecrystalline composition or the pharmaceutical composition prevents thesymptom of pain experienced by the subject. In some embodiments, theadministration of the crystalline composition or the pharmaceuticalcomposition eliminates the symptom of pain experienced by the subject.

In various embodiments of the methods as described herein, thecrystalline composition or the pharmaceutical composition isadministered at a dose from about 5 mg/day to about 1000 mg/day. In someembodiments, the crystalline composition or the pharmaceuticalcomposition is administered in a fed state. In some embodiments, thecrystalline composition or the pharmaceutical composition isadministered in a fasted state. In some embodiments, the crystallinecomposition or the pharmaceutical composition is administered at leastonce per day.

In various embodiments of the methods as described herein, the methodfurther comprises administering to the subject an additionalchemotherapeutic agent. In some embodiments, the additionalchemotherapeutic agent is glucocorticoid, a mineralocorticoid, an ACAT1inhibitor, or an anti-androgen agent. In some embodiments, theglucocorticoid is beclomethasone, betamethasone, budesonide, cortisone,dexamethasone, hydrocortisone, methylprednisolone, prednisolone,prednisone, or triamcinolone. In some embodiments, the mineralocorticoidis fludrocortisone. In some embodiments, the additional chemotherapeuticagent is another CRF1antagonist.

In various embodiments of the methods as described herein, the methodfurther comprises an additional treatment selected from surgicalresection of the tumors and radiation therapy, or a combination thereof.In some embodiments, the additional therapy is surgical resection andthe surgical resection is prior to, after, and/or concurrent withadministration of the crystalline composition as described herein, orthe pharmaceutical composition comprising the crystalline composition asdescribed herein. In some embodiments, the additional therapy isradiation therapy and the radiation therapy is prior to, after, and/orconcurrent with administration of the crystalline composition asdescribed herein, or the pharmaceutical composition comprising thecrystalline composition as described herein.

In various embodiments of the methods, the subject is from about 9 yearsof age to about 18 years of age. In some embodiments, the subject isfrom about 8 years of age to about 55 years of age.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference in their entiretiesto the same extent as if each individual publication, patent, or patentapplication was specifically and individually indicated to beincorporated by reference.

DESCRIPTION OF THE DRAWINGS

The novel features of the present disclosure are set forth withparticularity in the appended claims. An understanding of the featuresand advantages of the present disclosure may be obtained by reference tothe following detailed description that sets forth illustrativeembodiments, in which the principles of the present disclosure areutilized, and the accompanying drawings of which:

FIG. 1 shows the X-ray powder diffraction (XRPD) pattern for thecrystalline composition according to Formula I.

FIG. 2 shows the differential scanning calorimetry (DSC) thermogram forthe crystalline composition according to Formula I.

FIG. 3 shows the thermogravimetric analysis (TGA) thermogram for thecrystalline composition according to Formula I.

FIG. 4 shows the dynamic vapor sorption (DVS) trace for the crystallinecomposition according to Formula I.

FIG. 5 shows the infrared (IR) spectrum for the crystalline compositionaccording to Formula I.

FIG. 6 shows the proton nuclear magnetic resonance (¹H NMR) spectrum forthe crystalline composition according to Formula I.

FIG. 7 shows the Raman spectrum for the crystalline compositionaccording to Formula I.

DETAILED DESCRIPTION OF THE INVENTION

4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholine(Compound 1) is a potent antagonist of Corticotropin-releasing hormonereceptor 1 (CRF1). CRF1 antagonists are useful in the treatment ofvarious diseases, conditions, and disorders for which abnormal CRF1activity plays a role.

Crystalline forms of a small molecule drug candidate, such as a CRF1antagonist, can have different physical properties, including meltingpoint, apparent solubility, dissolution rate, optical and mechanicalproperties, vapor pressure, and density. These properties can have adirect effect on the ability to process or manufacture a drug substanceand the drug product. Moreover, differences in these properties can andoften lead to different pharmacokinetics profiles for differentpolymorphic forms of a drug. Polymorphism can affect the quality,safety, and/or efficacy of a drug product, such as a CRF1 antagonist.Thus, there still remains a need for crystalline compositions of CRF1antagonist. The present disclosure addresses this need and providesrelated advantages as well.

Compound 1

As described herein, Compound 1 refers to4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholine,which has the chemical structure as shown below:

Compound 1 is a CRF1 modulator. CRF1 modulator, such as a CRF1antagonist or inhibitor, are useful in the treatment of variousconditions and disorders that are mediated by CRF1 activities.

In some embodiments, the present disclosure provides a crystallinecomposition comprising compound 1. In some embodiments, the crystallinecomposition comprises Compound 1 and oxalic acid in a molar ratio of2:1.

As used herein, “crystalline,” “crystalline form,” “polymorph,” “Form,”and “form” may be used interchangeably herein, and are meant to includeall crystalline and amorphous forms of the compound, including, forexample, co-crystals, polymorphs, pseudopolymorphs, salts, solvates,hydrates, unsolvated polymorphs (including anhydrates), conformationalpolymorphs, and amorphous forms, as well as mixtures thereof, unless aparticular crystalline or amorphous form is referred to. Compounds ofthe present disclosure include crystalline and amorphous forms of thosecompounds, including, for example, polymorphs, co-crystals,pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (includinganhydrates), conformational polymorphs, and amorphous forms of thecompounds, as well as mixtures thereof.

As used herein, “co-crystal” may be used to describe crystallinecompositions comprising multi-component crystals based on hydrogenbonding interactions of hydrogen ions to form salt forms. In someembodiments, the crystalline composition as described herein areco-crystals comprising oxalic acid and Compound 1.

Definitions

A “pharmaceutically acceptable carrier” refers to an ingredient in apharmaceutical formulation, other than an active ingredient, which isnontoxic to a subject. A pharmaceutically acceptable carrier includes,but is not limited to, a buffer, excipient, stabilizer, or preservative,such as those known in the art, for example, described in Remington'sPharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results including and preferably clinical results.For example, beneficial or desired clinical results include, but are notlimited to, one or more of the following: decreasing symptoms resultingfrom the disease, increasing the quality of life of those suffering fromthe disease, decreasing the dose of other medications required to treatthe disease, delaying the progression of the disease, and/or prolongingsurvival of individuals.

As used herein, “delaying development of a disease” means to defer,hinder, slow, retard, stabilize, and/or postpone development of thedisease (such as cancer). This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease. For example, a late stage cancer, such asdevelopment of metastasis, may be delayed.

As used herein, an “effective dosage” or “effective amount” of drug,compound, or pharmaceutical composition is an amount sufficient toeffect beneficial or desired results. For prophylactic use, beneficialor desired results include results such as eliminating or reducing therisk, lessening the severity, or delaying the onset of the disease,including biochemical, histological and/or behavioral symptoms of thedisease, its complications and intermediate pathological phenotypespresenting during development of the disease. For therapeutic use,beneficial or desired results include clinical results such asdecreasing one or more symptoms resulting from the disease, increasingthe quality of life of those suffering from the disease, decreasing thedose of other medications required to treat the disease, enhancingeffect of another medication such as via targeting, delaying theprogression of the disease, and/or prolonging survival. In the case ofcancer or tumor, an effective amount of the drug may have the effect inreducing the number of cancer cells; reducing the tumor size; inhibiting(i.e., slow to some extent and preferably stop) cancer cell infiltrationinto peripheral organs; inhibit (i.e., slow to some extent andpreferably stop) tumor metastasis; inhibiting, to some extent, tumorgrowth; and/or relieving to some extent one or more of the symptomsassociated with the disorder. An effective dosage can be administered inone or more administrations. For purposes of this invention, aneffective dosage of drug, compound, or pharmaceutical composition is anamount sufficient to accomplish prophylactic or therapeutic treatmenteither directly or indirectly. As is understood in the clinical context,an effective dosage of a drug, compound, or pharmaceutical compositionmay or may not be achieved in conjunction with another drug, compound,or pharmaceutical composition. Thus, an “effective dosage” may beconsidered in the context of administering one or more therapeuticagents, and a single agent may be considered to be given in an effectiveamount if, in conjunction with one or more other agents, a desirableresult may be or is achieved.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor interaction meansnegatively affecting (e.g. decreasing) the activity or function of theprotein relative to the activity or function of the protein in theabsence of the inhibitor. Inhibition may refer to reduction of a diseaseor symptoms of disease. Inhibition may refer to a reduction in theactivity of a particular protein or nucleic acid target. The protein maybe deoxycytidine kinase. Thus, inhibition includes, at least in part,partially or totally blocking stimulation, decreasing, preventing, ordelaying activation, or inactivating, desensitizing, or down-regulatingsignal transduction or enzymatic activity or the amount of a protein.

The term “modulator” refers to a composition that increases or decreasesthe level of a target molecule or the function of a target molecule orthe physical state of the target of the molecule.

The term “modulate” is used in accordance with its plain ordinarymeaning and refers to the act of changing or varying one or moreproperties. “Modulation” refers to the process of changing or varyingone or more properties. For example, a modulator of a target proteinchanges by increasing or decreasing a property or function of the targetmolecule or the amount of the target molecule. A modulator of a diseasedecreases a symptom, cause, or characteristic of the targeted disease.

“Selective” or “selectivity” or the like of a compound refers to thecompound's ability to discriminate between molecular targets.

“Specific”, “specifically”, “specificity”, or the like of a compoundrefers to the compound's ability to cause a particular action, such asinhibition, to a particular molecular target with minimal or no actionto other proteins in the cell.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,parenteral, intraperitoneal, intramuscular, intralesional, intrathecal,intranasal or subcutaneous administration, or the implantation of aslow-release device, e.g., a mini-osmotic pump, to a subject.Administration is by any route, including parenteral and transmucosal(e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, ortransdermal). Parenteral administration includes, e.g., intravenous,intramuscular, intra-arteriole, intradermal, subcutaneous,intraperitoneal, intraventricular, and intracranial. Other modes ofdelivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc.

By “co-administer” it is meant that a compound described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies, for example, ananticancer agent as described herein. The compounds described herein canbe administered alone or can be co-administered to the patient.Co-administration is meant to include simultaneous or sequentialadministration of the compound individually or in combination (more thanone compound or agent). Thus, the preparations can also be combined,when desired, with other active substances (e.g. anticancer agents).

Co-administration includes administering one active agent (e.g. acomplex described herein) within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or24 hours of a second active agent (e.g. anti-cancer agents). Alsocontemplated herein, are embodiments, where co-administration includesadministering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16,20, or 24 hours of a second active agent. Co-administration includesadministering two active agents simultaneously, approximatelysimultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes ofeach other), or sequentially in any order. Co-administration can beaccomplished by co-formulation, i.e., preparing a single pharmaceuticalcomposition including both active agents. In other embodiments, theactive agents can be formulated separately. In some embodiments, theactive and/or adjunctive agents are linked or conjugated to one another.In some embodiments, the compounds described herein are combined withtreatments for cancer such as chemotherapy or radiation therapy.

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease means thatthe disease is caused by (in whole or in part), a symptom of the diseaseis caused by (in whole or in part) the substance or substance activityor function, or a side-effect of the compound (e.g. toxicity) is causedby (in whole or in part) the substance or substance activity orfunction.

“Patient,” “subject,” “patient in need thereof,” and “subject in needthereof” are herein used interchangeably and refer to a living organismsuffering from or prone to a disease or condition that can be treated byadministration of a pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals, bovines, rats,mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammaliananimals. In some embodiments, a patient is human. A “cancer-patient” isa patient suffering from, or prone to developing cancer.

Unless clearly indicated otherwise, the term “individual” as used hereinrefers to a mammal, including but not limited to, bovine, horse, feline,rabbit, canine, rodent, or primate (e.g., human). In some embodiments,an individual is a human. In some embodiments, an individual is anon-human primate such as chimpanzees and other apes and monkey species.In some embodiments, an individual is a farm animal such as cattle,horses, sheep, goats and swine; pets such as rabbits, dogs and cats;laboratory animals including rodents, such as rats, mice, and guineapigs; and the like. In some embodiments, the invention find use in bothhuman medicine and in the veterinary context.

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with the compounds ormethods provided herein. In some embodiments, the disease as used hereinrefers to cancer.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural reference unless the context clearly indicatesotherwise.

It is understood that aspect and variations of the invention describedherein include “consisting” and/or “consisting essentially of” aspectsand variations.

Crystalline Composition According to Formula I

The crystalline composition prepared according to the methods of thepresent disclosure may be characterized by any methodology according tothe art. For example, the crystalline composition according to Formula Iprepared according to the methods of the present disclosure may becharacterized by X-ray powder diffraction (XRPD), differential scanningcalorimetry (DSC), thermogravimetric analysis (TGA), and/or spectroscopy(e.g., Raman, solid state nuclear magnetic resonance (ssNMR), protonnuclear magnetic resonance (¹H NMR), and infrared (IR)). In someembodiments, crystallinity of the solid form is determined by X-RayPowder Diffraction (XPRD).

XRPD: Crystalline composition according to the present disclosure may becharacterized by XRPD. The relative intensities of XRPD peaks can vary,depending upon the particle size, the sample preparation technique, thesample mounting procedure and the particular instrument employed.Moreover, instrument variation and other factors can affect the 2-θvalues. Therefore, the XRPD peak assignments can vary, for example byplus or minus about 0.2 degrees.

DSC: Crystalline composition according to the present disclosure canalso be identified by its characteristic DSC thermograms such as shownin FIG. 2 . For DSC, it is known that the temperatures observed willdepend upon the rate of temperature change as well as sample preparationtechnique and the particular instrument employed. Thus, the valuesreported herein relating to DSC thermograms can vary, for example byplus or minus about 4° C.

TGA: Crystalline composition according to the present disclosure mayalso give rise to thermal behavior different from that of the amorphousmaterial or other crystalline forms. Thermal behavior may be measured inthe laboratory by thermogravimetric analysis (TGA) which may be used todistinguish some crystalline forms from others. In one aspect, thecrystalline composition as described herein may be characterized bythermogravimetric analysis.

DVS: Crystalline composition according to the present disclosure mayalso give rise to vapors sorption behavior different from that of theamorphous material or other crystalline forms. The vapor sorptionbehavior may be measured in the laboratory by dynamic vapor sorption(DVS) which may be used to distinguish some crystalline forms fromothers. In one aspect, the crystalline composition as described hereinmay be characterized by dynamic vapor sorption.

The crystalline composition comprising Compound 1, e.g. according toFormula I, are useful in the production of medicinal preparations andcan be obtained by means of a crystallization process to producecrystalline and semi-crystalline forms or a solidification process toobtain the amorphous form. In various embodiments, the crystallizationis carried out by either generating the desired compound (for exampleCompound 1) in a reaction mixture and isolating the desired crystallinecomposition from the reaction mixture, or by dissolving raw compound ina solvent, optionally with heat, followed by crystallizing/solidifyingthe product by cooling (including active cooling) and/or by the additionof an antisolvent for a period of time. The crystallization orsolidification may be followed by drying carried out under controlledconditions until the desired water content is reached in the endcrystalline composition.

FIG. 1 shows the X-ray powder diffraction (XRPD) pattern for thecrystalline composition according to Formula I.

FIG. 2 shows the differential scanning calorimetry (DSC) thermogram forthe crystalline composition according to Formula I.

FIG. 3 shows the thermogravimetric analysis (TGA) thermogram for thecrystalline composition according to Formula I.

FIG. 4 shows the dynamic vapor sorption (DVS) trace for the crystallinecomposition according to Formula I.

FIG. 5 shows the infrared (IR) spectrum for the crystalline compositionaccording to Formula I.

FIG. 6 shows the proton nuclear magnetic resonance (¹H NMR) spectrum forthe crystalline composition according to Formula I.

FIG. 7 shows the Raman spectrum for the crystalline compositionaccording to Formula I.

In a first aspect, the present disclosure provides a crystallinecomposition according Formula I:

In some embodiments, the crystals of the crystalline compositionaccording to Formula I have unit cell parameters at T=150° K of:a=34.003(4) Å, b=6.5843(13) Å, c=21.062(5) Å; R=108.703(12°),V=4466.5(15) Å³ and a monoclinic C2/c space group.

In some embodiments, the crystals of the crystalline compositionaccording to Formula I is characterized by:

-   -   (a) an X-ray powder diffraction pattern comprising peaks at        10.84±0.2° 2-θ, 15.96±0.2° 2-θ, 23.44±0.2° 2-θ, and 24.80±0.2°        2-θ, and as measured by X-ray powder diffraction using an X-ray        wavelength of 0.71073 Å;    -   (b) an X-ray powder diffraction pattern substantially the same        as shown in FIG. 1 ;    -   (c) a differential scanning calorimetry (DSC) thermogram        comprising an endotherm in the range of about 160° C. to 170°        C.;    -   (d) a differential scanning calorimetry (DSC) thermogram        comprising an endotherm with an onset of about 164° C. and a        peak of about 166° C.;    -   (e) a differential scanning calorimetry (DSC) thermogram        substantially the same as shown in FIG. 2 ;    -   (f) a thermogravimetric analysis (TGA) thermogram comprising a        loss in mass of about 11% over a temperature range of about        25° C. to about 200° C.;    -   (g) a thermogravimetric analysis (TGA) thermogram substantially        the same as shown in FIG. 3 ; or    -   (h) combinations thereof.

In some embodiments, the crystalline composition according to Formula Iis characterized by an X-ray powder diffraction pattern comprising peaksat 10.84±0.2° 2-θ, 15.96±0.2° 2-θ, 23.44±0.2° 2-θ, and 24.80±0.2° 2-θ,and as measured by X-ray powder diffraction using an X-ray wavelength of0.71073 Å. In some embodiments, the crystalline composition according toFormula I is characterized by an X-ray powder diffraction patterncomprising peaks at 10.84±0.1° 2-θ, 15.96±0.1° 2-θ, 23.44±0.1° 2-0, and24.80±0.1° 2-0, and as measured by X-ray powder diffraction using anX-ray wavelength of 0.71073 Å. In some embodiments, the crystallinecomposition according to Formula I is characterized by an X-ray powderdiffraction pattern comprising peaks at about 10.84° 2-θ, about 15.96°2-θ, about 23.44° 2-θ, and about 24.80° 2-θ, and as measured by X-raypowder diffraction using an X-ray wavelength of 0.71073 Å.

In some embodiments, the X-ray powder diffraction pattern furthercomprising at least one peak selected from 5.44±0.2° 2-θ, 20.78±0.2°2-θ, 22.74±0.2° 2-θ, 23.04±0.2° 2-θ, 26.80±0.2° 2-θ, and 28.86±0.2° 2-θ,and as measured by X-ray powder diffraction using an X-ray wavelength of0.71073 Å. In some embodiments, the X-ray powder diffraction patternfurther comprising at least one peak selected from 5.44±0.1° 2-θ,20.78±0.1° 2-θ, 22.74±0.1θ 2-θ, 23.04±0.1° 2-θ, 26.80±0.1° 2-0, and28.86±0.1° 2-0, and as measured by X-ray powder diffraction using anX-ray wavelength of 0.71073 Å. In some embodiments, the X-ray powderdiffraction pattern further comprising at least one peak selected fromabout 5.44° 2-θ, about 20.78° 2-θ, about 22.74° 2-θ, about 23.04° 2-θ,about 26.80° 2-θ, and about 28.86° 2-θ, and as measured by X-ray powderdiffraction using an X-ray wavelength of 0.71073 Å.

In some embodiments, the X-ray powder diffraction pattern furthercomprising at least one peak selected from 8.82±0.2° 2-θ, 11.70±0.2°2-θ, 14.60±0.2° 2-θ, 15.56±0.2° 2-θ, 16.70±0.2° 2-θ, 18.82±0.2° 2-θ,19.18±0.2° 2-θ, 20.02±0.2° 2-θ, 20.50±0.2° 2-θ, 21.72±0.2° 2-θ,25.52±0.2° 2-θ, 25.92±0.2° 2-θ, 26.94±0.2° 2-θ, and 28.00±0.2° 2-θ, andas measured by X-ray powder diffraction using an X-ray wavelength of0.71073 Å. In some embodiments, the X-ray powder diffraction patternfurther comprising at least two peaks selected from 8.82±0.2° 2-θ,11.70±0.2° 2-θ, 14.60±0.2° 2-θ, 15.56±0.2° 2-θ, 16.70±0.2° 2-θ,18.82±0.2° 2-θ, 19.18±0.2° 2-θ, 20.02±0.2° 2-θ, 20.50±0.2° 2-θ,21.72±0.2° 2-θ, 25.52±0.2° 2-θ, 25.92±0.2° 2-θ, 26.94±0.2° 2-θ, and28.00±0.2° 2-θ, and as measured by X-ray powder diffraction using anX-ray wavelength of 0.71073 Å. In some embodiments, the X-ray powderdiffraction pattern further comprising at least three peaks selectedfrom 8.82±0.2° 2-θ, 11.70±0.2° 2-θ, 14.60±0.2° 2-θ, 15.56±0.2° 2-θ,16.70±0.2° 2-θ, 18.82±0.2° 2-θ, 19.18±0.2° 2-θ, 20.02±0.2° 2-θ,20.50±0.2° 2-θ, 21.72±0.2° 2-θ, 25.52±0.2° 2-θ, 25.92±0.2° 2-θ,26.94±0.2° 2-θ, and 28.00±0.2° 2-θ, and as measured by X-ray powderdiffraction using an X-ray wavelength of 0.71073 Å. In some embodiments,the X-ray powder diffraction pattern further comprising at least fourpeaks selected from 8.82±0.2° 2-θ, 11.70±0.2° 2-θ, 14.60±0.2° 2-θ,15.56±0.2° 2-θ, 16.70±0.2° 2-θ, 18.82±0.2° 2-θ, 19.18±0.2° 2-θ,20.02±0.2° 2-θ, 20.50±0.2° 2-θ, 21.72±0.2° 2-θ, 25.52±0.2° 2-θ,25.92±0.2° 2-θ, 26.94±0.2° 2-θ, and 28.00±0.2° 2-θ, and as measured byX-ray powder diffraction using an X-ray wavelength of 0.71073 Å. In someembodiments, the X-ray powder diffraction pattern further comprising atleast five peaks selected from 8.82±0.2° 2-θ, 11.70±0.2° 2-θ, 14.60±0.2°2-θ, 15.56±0.2° 2-θ, 16.70±0.2° 2-θ, 18.82±0.2° 2-θ, 19.18±0.2° 2-θ,20.02±0.2° 2-θ, 20.50±0.2° 2-θ, 21.72±0.2° 2-θ, 25.52±0.2° 2-θ,25.92±0.2° 2-θ, 26.94±0.2° 2-θ, and 28.00±0.2° 2-θ, and as measured byX-ray powder diffraction using an X-ray wavelength of 0.71073 Å. In someembodiments, the X-ray powder diffraction pattern further comprising atleast six peaks selected from 8.82±0.2° 2-θ, 11.70±0.2° 2-θ, 14.60±0.2°2-θ, 15.56±0.2° 2-θ, 16.70±0.2° 2-θ, 18.82±0.2° 2-θ, 19.18±0.2° 2-θ,20.02±0.2° 2-θ, 20.50±0.2° 2-θ, 21.72±0.2° 2-θ, 25.52±0.2° 2-θ,25.92±0.2° 2-θ, 26.94±0.2° 2-θ, and 28.00±0.2° 2-θ, and as measured byX-ray powder diffraction using an X-ray wavelength of 0.71073 Å. In someembodiments, the X-ray powder diffraction pattern further comprising atleast seven peaks selected from 8.82±0.2° 2-θ, 11.70±0.2° 2-θ,14.60±0.2° 2-θ, 15.56±0.2° 2-θ, 16.70±0.2° 2-θ, 18.82±0.2° 2-θ,19.18±0.2° 2-θ, 20.02±0.2° 2-θ, 20.50±0.2° 2-θ, 21.72±0.2° 2-θ,25.52±0.2° 2-θ, 25.92±0.2° 2-θ, 26.94±0.2° 2-θ, and 28.00±0.2° 2-θ, andas measured by X-ray powder diffraction using an X-ray wavelength of0.71073 Å. In some embodiments, the X-ray powder diffraction patternfurther comprising at least eight peaks selected from 8.82±0.2° 2-θ,11.70±0.2° 2-θ, 14.60±0.2° 2-θ, 15.56±0.2° 2-θ, 16.70±0.2° 2-θ,18.82±0.2° 2-θ, 19.18±0.2° 2-θ, 20.02±0.2° 2-θ, 20.50±0.2° 2-θ,21.72±0.2° 2-θ, 25.52±0.2° 2-θ, 25.92±0.2° 2-θ, 26.94±0.2° 2-θ, and28.00±0.2° 2-θ, and as measured by X-ray powder diffraction using anX-ray wavelength of 0.71073 Å. In some embodiments, the X-ray powderdiffraction pattern comprises peaks selected from 8.82±0.1° 2-θ,11.70±0.1° 2-0, 14.60±0.1° 2-θ, 15.56±0.1° 2-θ, 16.70±0.1° 2-θ,18.82±0.1° 2-θ, 19.18±0.1° 2-θ, 20.02±0.1° 2-θ, 20.50±0.1° 2-θ,21.72±0.1° 2-θ, 25.52±0.1° 2-θ, 25.92±0.1° 2-θ, 26.94±0.1° 2-0, and28.00±0.1° 2-0, and as measured by X-ray powder diffraction using anX-ray wavelength of 0.71073 Å. In some embodiments, the X-ray powderdiffraction pattern comprises peaks selected from 8.82° 2-θ, 11.70° 2-θ,14.60° 2-θ, 15.56° 2-θ, 16.70° 2-θ, 18.82° 2-θ, 19.18° 2-θ, 20.02° 2-θ,20.50° 2-θ, 21.72° 2-θ, 25.52° 2-θ, 25.92° 2-θ, 26.94° 2-θ, and 28.00°2-θ, and as measured by X-ray powder diffraction using an X-raywavelength of 0.71073 Å.

In some embodiments, the crystalline composition according to Formula Iis characterized by a differential scanning calorimetry (DSC) thermogramcomprising an endotherm in the range of about 160° C. to 170° C. In someembodiments, the crystalline composition is characterized by adifferential scanning calorimetry (DSC) thermogram comprising anendotherm with an onset of about 164° C. and a peak of about 166° C. Insome embodiments, the crystalline composition is characterized by amelting point of about 166° C. In some embodiments, the crystallinecomposition is characterized by a differential scanning calorimetry(DSC) thermogram substantially the same as shown in FIG. 2 .

In some embodiments, the crystalline composition according to Formula Iis characterized by a differential scanning calorimetry (DSC) thermogramcomprising an endotherm at about 160° C. to about 170° C., about 160° C.to about 169° C., about 160° C. to about 168° C., about 160° C. to about167° C., about 160° C. to about 166° C., about 160° C. to about 165° C.,about 160° C. to about 164° C., about 160° C. to about 163° C., about160° C. to about 162° C., about 160° C. to about 161° C., about 161° C.to about 170° C., about 162° C. to about 170° C., about 163° C. to about170° C., about 164° C. to about 170° C., about 165° C. to about 170° C.,about 166° C. to about 170° C., about 167° C. to about 170° C., about168° C. to about 170° C., or about 169° C. to about 170° C. In someembodiments, the crystalline composition according to Formula I ischaracterized by a differential scanning calorimetry (DSC) thermogramcomprising an endotherm at about 162° C. to about 166° C., for exampleat about 162° C., about 163° C., about 164° C., 165° C., or 166° C. Insome embodiments, the crystalline composition is characterized by adifferential scanning calorimetry (DSC) thermogram comprising anendotherm at about 164° C. In some embodiments, the crystallinecomposition according for Formula I has a melting point of about 166° C.

In some embodiments, the crystalline composition according to Formula Iis characterized by a thermogravimetric analysis (TGA) thermogramcomprising a loss in mass of about 11% over a temperature range of about25° C. to about 200° C. In some embodiments, the crystalline compositiondecomposes above a temperature of about 50° C., about 100° C., about150° C., about 200° C., about 250° C., about 300° C., about 350° C., orabout 400° C. In some embodiments, the crystalline compositiondecomposes above a temperature of about 200° C. In some embodiments, thecrystalline composition decomposes above a temperature of about 250° C.In some embodiments, the crystalline composition is characterized by athermogravimetric analysis (TGA) thermogram substantially the same asshown in FIG. 3 .

In some embodiments, the crystalline composition according to Formula Iis characterized by a dynamic vapor sorption (DVS) trace substantiallythe same as shown in FIG. 4 .

In some embodiments, the crystalline composition according to Formula Iis anhydrous.

In some embodiments, the crystalline composition according to Formula Iis stable at room temperature. In some examples, the crystallinecomposition according to Formula I can be stored at room temperature foran extended period of time without significant chemical degradation orchange in the crystalline form. In some examples, crystallinecomposition according to Formula I can be stored at room temperature fora timer period of at least about 10 days, 30 days, 60 days, 90 days, 120days, 150 days, or 180 days. In some examples, the crystallinecomposition can be stored at room temperature for a time period of morethan about 180 days. In some examples, the crystalline composition canbe stored at room temperature for a time period of 10-14 days, 10-18days, 10-22 days, 10-26 days, 10-30 days, 10-40 days, 10-50 days, 10-60days, 10-90 days, 10-120 days, 10-150 days, 10-180 days, 14-18 days,14-22 days, 14-26 days, 14-30 days, 14-40 days, 14-50 days, 14-60 days,14-90 days, 14-120 days, 14-150 days, 14-180 days, 18-22 days, 18-26days, 18-30 days, 18-40 days, 18-50 days, 18-60 days, 18-90 days, 18-120days, 18-150 days, 18-180 days, 22-26 days, 22-30 days, 22-40 days,22-50 days, 22-60 days, 22-90 days, 22-120 days, 22-150 days, 22-180days, 26-30 days, 26-40 days, 26-50 days, 26-60 days, 26-90 days, 26-120days, 26-150 days, 26-180 days, 30-40 days, 30-50 days, 30-60 days,30-90 days, 30-120 days, 30-150 days, 30-180 days, 40-50 days, 40-60days, 40-90 days, 40-120 days, 40-150 days, 40-180 days, 50-60 days,50-90 days, 50-120 days, 50-150 days, 50-180 days, 60-90 days, 60-120days, 60-150 days, 60-180 days, 90-120 days, 90-150 days, or 90-180days. In some examples, the crystalline composition can be stored atroom temperature for a time period of at least 10 days, 14 days, 18days, 22 days, 26 days, 30 days, 40 days, 50 days, 60 days, 90 days, 120days, 150 days, or 180 days.

In some embodiments, the crystalline composition according to Formula Iis stable at room temperature or temperatures above the room temperatureand/or at high relative humidity (RH). In some examples, the crystallinecomposition can be stored at about 25° C. and at about 75% RH for anextended period of time without significant chemical degradation orchange in the crystalline form. In some examples, the crystallinecomposition according to Formula I can be stored at about 25° C. and atabout 75% RH for a time period of at least about 10 days, 30 days, 60days, 90 days, 120 days, 150 days, or 180 days. In some examples, thecrystalline composition can be stored at about 25° C. and at about 75%RH for a time period of 10-14 days, 10-18 days, 10-22 days, 10-26 days,10-30 days, 10-40 days, 10-50 days, 10-60 days, 10-90 days, 10-120 days,10-150 days, 10-180 days, 14-18 days, 14-22 days, 14-26 days, 14-30days, 14-40 days, 14-50 days, 14-60 days, 14-90 days, 14-120 days,14-150 days, 14-180 days, 18-22 days, 18-26 days, 18-30 days, 18-40days, 18-50 days, 18-60 days, 18-90 days, 18-120 days, 18-150 days,18-180 days, 22-26 days, 22-30 days, 22-40 days, 22-50 days, 22-60 days,22-90 days, 22-120 days, 22-150 days, 22-180 days, 26-30 days, 26-40days, 26-50 days, 26-60 days, 26-90 days, 26-120 days, 26-150 days,26-180 days, 30-40 days, 30-50 days, 30-60 days, 30-90 days, 30-120days, 30-150 days, 30-180 days, 40-50 days, 40-60 days, 40-90 days,40-120 days, 40-150 days, 40-180 days, 50-60 days, 50-90 days, 50-120days, 50-150 days, 50-180 days, 60-90 days, 60-120 days, 60-150 days,60-180 days, 90-120 days, 90-150 days, or 90-180 days. In some examples,the crystalline composition according to Formula I can be stored atabout 25° C. for a time period of at least 10 days, 14 days, 18 days, 22days, 26 days, 30 days, 40 days, 50 days, 60 days, 90 days, 120 days,150 days, or 180 days.

In some embodiments, the crystalline composition according to Formula Iis thermodynamically stable.

In some embodiments, the crystalline composition according to Formula Iis highly bioavailable.

In some embodiments, the crystalline composition according to Formula Iis stable under accelerated storage conditions.

In some embodiments, the crystalline composition according to Formula Iis characterized by an infrared (IR) spectrum substantially the same asshown in FIG. 5 .

In some embodiments, the crystalline composition according to Formula Iis characterized by a proton nuclear magnetic resonance (¹H NMR)spectrum substantially the same as shown in FIG. 6 .

In some embodiments, the crystalline composition according to Formula Iis characterized by a Raman spectrum substantially the same as shown inFIG. 7 .

Compositions and Formulations

In a second aspect, the present disclosure provides a pharmaceuticalcomposition comprising a crystalline composition according to Formula I:

and at least one pharmaceutically acceptable carrier or excipient.

Dosage Form

In some embodiments, the pharmaceutical composition described herein isprovided in unit dosage form. As used herein, a “unit dosage form” is acomposition containing an amount of the crystalline compositionaccording to Formula I that is suitable for administration to a subjectin a single dose. Such dosage forms are contemplated to be administeredonce, twice, thrice or more per day and may be administered as infusionover a period of time (e.g., from about 30 minutes to about 2-6 hours),or administered as a continuous infusion, and may be given more thanonce during a course of therapy, though a single administration is notspecifically excluded.

In some embodiments, the pharmaceutical compositions described hereinare formulated as oral dosage forms. Suitable oral dosage forms include,for example, tablets, pills, sachets, or capsules. In some embodiments,the pharmaceutical composition comprises one or more additionalpharmaceutically acceptable excipients. See, e.g., Remington: TheScience and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co.,Easton, PA (2005) for a list of pharmaceutically acceptable excipients.

Capsule

In some embodiments, the pharmaceutical composition comprising thecrystalline composition according to Formula I is formulated as acapsule. In some embodiments, the pharmaceutical composition isencapsulated in a hard gel capsule. In some embodiments, thepharmaceutical composition is encapsulated in a soft gel capsule. Insome embodiments, the pharmaceutical composition is formulated as a hardgel capsule. In some embodiments, the pharmaceutical composition isformulated as a soft gel capsule.

In some embodiments, the capsule is formed using materials whichinclude, but are not limited to, natural or synthetic gelatin, pectin,casein, collagen, protein, modified starch, polyvinylpyrrolidone,acrylic polymers, cellulose derivatives, or any combinations thereof. Insome embodiments, the capsule is formed using preservatives, coloringand opacifying agents, flavorings and sweeteners, sugars,gastroresistant substances, or any combinations thereof. In someembodiments, the capsule is coated. In some embodiments, the coatingcovering the capsule includes, but is not limited to, immediate releasecoatings, protective coatings, enteric or delayed release coatings,sustained release coatings, barrier coatings, seal coatings, orcombinations thereof. In some embodiments, a capsule herein is hard orsoft. In some embodiments, the capsule is seamless. In some embodiments,the capsule is broken such that the particulates are sprinkled on softfoods and swallowed without chewing. In some embodiments, the shape andsize of the capsule also vary. Examples of capsule shapes include, butare not limited to, round, oval, tubular, oblong, twist off, or anon-standard shape. The size of the capsule may vary according to thevolume of the particulates. In some embodiments, the size of the capsuleis adjusted based on the volume of the particulates and powders. Hard orsoft gelatin capsules may be manufactured in accordance withconventional methods as a single body unit comprising the standardcapsule shape. A single-body soft gelatin capsule typically may beprovided, for example, in sizes from 3 to 22 minims (1 minims beingequal to 0.0616 ml) and in shapes of oval, oblong or others. The gelatincapsule may also be manufactured in accordance with conventionalmethods, for example, as a two-piece hard gelatin capsule, sealed orunsealed, typically in standard shape and various standard sizes,conventionally designated as (000), (00), (0), (1), (2), (3), (4), and(5). The largest number corresponds to the smallest size. In someembodiments, the pharmaceutical composition described herein (e.g.,capsule) is swallowed as a whole.

In some embodiments, the capsule comprises one or more pharmaceuticallyacceptable excipients. In some embodiments, the capsule is free ofadditional excipients.

Tablet

In some embodiments, the pharmaceutical composition comprising thecrystalline composition according to Formula I is formulated as atablet.

In some embodiments, the tablet size is less than about 1000 mg, lessthan about 800 mg, less than about 600 mg, less than about 400 mg orless than about 200 mg. In some embodiments, the tablet has a dosestrength of more than about 50 mg, more than about 100 mg, more thanabout 150 mg, more than about 200 mg, or more than about 250 mg. In someembodiments, the tablet size is less than about 1000 mg for a dosestrength of more than about 50 mg. In some embodiments, the tablet sizeis less than 800 mg for a dose strength of more than about 100 mg. Insome embodiments, the tablet size is less than 600 mg for a dosestrength of more than about 150 mg. In some embodiment, the tablet sizeis less than 400 mg for a dose strength of more than about 200 mg. Insome embodiments, the tablet size is less than 400 mg for a dosestrength of 200 mg.

In some embodiments, more than about 20% of the tablet is dissolved inconventional dissolution media. In some embodiments, more than about 40%of the tablet is dissolved in conventional dissolution media. In someembodiments, more than about 50% of the tablet is dissolved inconventional dissolution media. In some embodiments, more than about 60%of the tablet is dissolved in conventional dissolution media. In someembodiments, more than about 70% of the tablet is dissolved inconventional dissolution media. In some embodiments, more than about 80%of the tablet is dissolved in conventional dissolution media. In someembodiments, more than about 20% of the tablet is dissolved in less than24 hours in conventional dissolution media. In some embodiments, morethan about 20% of the tablet is dissolved in less than 12 hours inconventional dissolution media. In some embodiments, more than about 20%of the tablet is dissolved in less than 6 hours in conventionaldissolution media. In some embodiments, more than about 20% of thetablet is dissolved in less than 3 hours in conventional dissolutionmedia. In some embodiments, more than about 20% of the tablet isdissolved in less than 2 hours in conventional dissolution media. Insome embodiments, more than about 20% of the tablet is dissolved in lessthan 60 minutes in conventional dissolution media. In some embodiments,more than about 40% of the tablet is dissolved in less than 60 minutesin conventional dissolution media. In some embodiments, more than about50% of the tablet is dissolved in less than 60 minutes in conventionaldissolution media. In some embodiments, more than about 60% of thetablet is dissolved in less than 60 minutes in conventional dissolutionmedia. In some embodiments, more than about 70% of the tablet isdissolved in less than 60 minutes in conventional dissolution media. Insome embodiments, more than about 80% of the tablet is dissolved in lessthan 60 minutes in conventional dissolution media. In some embodiments,more than 70% of the tablet is dissolved in 60 minutes in conventionaldissolution media.

In some embodiments, the tablet is produced at a commercial scale.

In some embodiments, the tablet comprises one or more pharmaceuticallyacceptable excipients.

In some embodiments, the tablet is coated with a coating material, e.g.,a sealant. In some embodiments, the coating material is water soluble.In some embodiments, the coating material comprises a polymer,plasticizer, a pigment, or any combination thereof. In some embodiments,the coating material is in the form of a film coating, e.g., a glossyfilm, a pH independent film coating, an aqueous film coating, a drypowder film coating (e.g., complete dry powder film coating), or anycombination thereof. In some embodiments, the coating material is highlyadhesive. In some embodiments, the coating material provides low levelof water permeation. In some embodiments, the coating material providesoxygen barrier protection. In some embodiments, the coating materialallows immediate disintegration for fast release of Compound 1. In someembodiments, the coating material is pigmented, clear, or white. In someembodiments, the coating is an enteric coating. Exemplary coatingmaterials include, without limitation, polyvinylpyrrolidone, polyvinylalcohol, an acrylate-methacrylic acid copolymer, amethacrylate-methacrylic acid copolymer, cellulose acetate phthalate,cellulose acetate succinate, hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, polyvinyl acetatephthalate, shellac, cellulose acetate trimellitate, sodium alginate,zein, and any combinations thereof.

Oral Dosage Forms

In some embodiments, the pharmaceutical composition comprising thecrystalline composition according to Formula I is formulated as an oraldosage form. In some embodiments, the oral dosage form is selected fromthe group consisting of a tablet, a capsule, a buccal tablet, asub-lingual table, an orally-disintegrating tablet, a thin film, aliquid solution, a liquid suspension, a syrup, a powder, and solidcrystals. In some embodiment, the oral dosage form is selected from thegroup consisting of a tablet, a capsule, a buccal tablet, a sub-lingualtable, an orally-disintegrating tablet, a thin film, a liquid solution,a liquid suspension, a syrup, a powder, solid crystals, minitabs, coatedpellets and sachets.

Oral dosage forms may include capsules, tablets, pills, powders orgranules. Such forms may include forms that dissolve or disintegratequickly in the oral environment. Such forms may be prepared withcoatings and shells. In some embodiments, these oral dosage forms arecapable of controlled or sustained release.

Pharmaceutically Acceptable Excipients

In some embodiments, the pharmaceutical composition comprising thecrystalline composition according to Formula I comprises apharmaceutically acceptable excipient. In some embodiments, thepharmaceutical composition is free of pharmaceutically acceptableexcipients. The term “pharmaceutically acceptable excipient”, as usedherein, means one or more compatible solid or encapsulating substances,which are suitable for administration to a mammal. The term“compatible”, as used herein, means that the components of thecomposition are capable of being commingled with the subject compound,and with each other, in a manner such that there is no interaction,which would substantially reduce the pharmaceutical efficacy of thecomposition under ordinary use situations. In some embodiments, thepharmaceutically acceptable excipient is of sufficiently high purity andsufficiently low toxicity to render them suitable for administrationpreferably to an animal, preferably mammal, being treated.

Some examples of substances, which can serve as pharmaceuticallyacceptable excipients include:

-   -   Amino acids such as alanine, arginine, asparagine, aspartic        acid, cysteine, glutamine, glutamic acid, glycine, histidine,        isoleucine, leucine, lysine, methionine, phenylalanine, proline,        serine, threonine, tryptophan, tyrosine, and valine. In some        embodiments, the amino acid is arginine. In some embodiments,        the amino acid is L-arginine.    -   Monosaccharides such as glucose (dextrose), arabinose, mannitol,        fructose (levulose), and galactose.    -   Cellulose and its derivatives such as sodium carboxymethyl        cellulose, ethyl cellulose, and methyl cellulose.    -   Solid lubricants such as talc, stearic acid, magnesium stearate        and sodium stearyl fumarate.    -   Polyols such as propylene glycol, glycerin, sorbitol, mannitol,        and polyethylene glycol.    -   Emulsifiers such as the polysorbates.    -   Wetting agents such as sodium lauryl sulfate, Tween®, Span,        alkyl sulphates, and alkyl ethoxylate sulphates.    -   Cationic surfactants such as cetrimide, benzalkonium chloride,        and cetylpyridinium chloride.    -   Diluents such as calcium carbonate, microcrystalline cellulose,        calcium phosphate, starch, pregelatinized starch, sodium        carbonate, mannitol, and lactose.    -   Binders such as starches (corn starch and potato starch),        gelatin, sucrose hydroxypropyl cellulose (HPC),        polyvinylpyrrolidone (PVP), and hydroxypropyl methyl cellulose        (HPMC).    -   Disintegrants such as starch, and alginic acid.    -   Super-disintegrants such as ac-di-sol, croscarmellose sodium,        sodium starch glycolate and crospovidone.    -   Glidants such as silicon dioxide.    -   Coloring agents such as the FD&C dyes.    -   Sweeteners and flavoring agents, such as aspartame, saccharin,        menthol, peppermint, and fruit flavors.    -   Preservatives such as benzalkonium chloride, PHMB,        chlorobutanol, thimerosal, phenylmercuric, acetate,        phenylmercuric nitrate, parabens, and sodium benzoate.    -   Tonicity adjustors such as sodium chloride, potassium chloride,        mannitol, and glycerin.    -   Antioxidants such as sodium bisulfite, acetone sodium bisulfite,        sodium formaldehyde, sulfoxylate, thiourea, and EDTA.    -   pH adjuster such as NaOH, sodium carbonate, sodium acetate, HCl,        and citric acid.    -   Cryoprotectants such as sodium or potassium phosphates, citric        acid, tartaric acid, gelatin, and carbohydrates such as        dextrose, mannitol, and dextran.    -   Surfactants such as sodium lauryl sulfate. For example, cationic        surfactants such as cetrimide (including tetradecyl trimethyl        ammonium bromide with dodecyl and hexadecyl compounds),        benzalkonium chloride, and cetylpyridinium chloride. Some        examples of anionic surfactants are alkylsulphates,        alkylethoxylate sulphates, soaps, carboxylate ions, sulfate        ions, and sulfonate ions. Some examples of non-ionic surfactants        are polyoxyethylene derivatives, polyoxypropylene derivatives,        polyol derivatives, polyol esters, polyoxyethylene esters,        poloxamers, glocol, glycerol esters, sorbitan derivatives,        polyethylene glycol (such as PEG-40, PEG-50, or PEG-55) and        esters of fatty alcohols.    -   Organic materials such as carbohydrates, modified carbohydrates,        lactose (including a-lactose, monohydrate spray dried lactose or        anhydrous lactose), starch, pregelatinized starch, sucrose,        mannitol, sorbital, cellulose (including powdered cellulose and        microcrystalline cellulose).    -   Inorganic materials such as calcium phosphates (including        anhydrous dibasic calcium phosphate, dibasic calcium phosphate        or tribasic calcium phosphate).    -   Co-processed diluents.    -   Compression aids.    -   Anti-tacking agents such as silicon dioxide and talc.

Amounts

In some embodiments, the pharmaceutical composition comprises betweenabout 1 mg and about 500 mg of the crystalline composition according toFormula I. In some embodiments, the pharmaceutical composition comprisesbetween about 1 mg and about 450 mg of the crystalline compositionaccording to Formula I. In some embodiments, the pharmaceuticalcomposition comprises between about 1 mg and about 400 mg of thecrystalline composition according to Formula I. In some embodiments, thepharmaceutical composition comprises between about 1 mg and about 350 mgof the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 1 mgand about 300 mg of the crystalline composition according to Formula I.In some embodiments, the pharmaceutical composition comprises betweenabout 1 mg and about 250 mg of the crystalline composition according toFormula I. In some embodiments, the pharmaceutical composition comprisesbetween about 1 mg and about 200 mg of the crystalline compositionaccording to Formula I. In some embodiments, the pharmaceuticalcomposition comprises between about 1 mg and about 175 mg of thecrystalline composition according to Formula I. In some embodiments, thepharmaceutical composition comprises between about 1 mg and about 150 mgof the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 1 mgand about 125 mg of the crystalline composition according to Formula I.In some embodiments, the pharmaceutical composition comprises betweenabout 1 mg and about 100 mg of the crystalline composition according toFormula I. In some embodiments, the pharmaceutical composition comprisesbetween about 1 mg and about 90 mg of the crystalline compositionaccording to Formula I. In some embodiments, the pharmaceuticalcomposition comprises between about 1 mg and about 80 mg of thecrystalline composition according to Formula I. In some embodiments, thepharmaceutical composition comprises between about 1 mg and about 70 mgof the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 1 mgand about 60 mg of the crystalline composition according to Formula I.In some embodiments, the pharmaceutical composition comprises betweenabout 1 mg and about 50 mg of the crystalline composition according toFormula I. In some embodiments, the pharmaceutical composition comprisesbetween about 1 mg and about 40 mg of the crystalline compositionaccording to Formula I. In some embodiments, the pharmaceuticalcomposition comprises between about 1 mg and about 30 mg of thecrystalline composition according to Formula I. In some embodiments, thepharmaceutical composition comprises between about 1 mg and about 20 mgof the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 1 mgand about 10 mg of the crystalline composition according to Formula I.In some embodiments, the pharmaceutical composition comprises betweenabout 1 mg and about 9 mg of the crystalline composition according toFormula I. In some embodiments, the pharmaceutical composition comprisesbetween about 1 mg and about 8 mg of the crystalline compositionaccording to Formula I. In some embodiments, the pharmaceuticalcomposition comprises between about 1 mg and about 7 mg of thecrystalline composition according to Formula I. In some embodiments, thepharmaceutical composition comprises between about 1 mg and about 6 mgof the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 1 mgand about 5 mg of the crystalline composition according to Formula I. Insome embodiments, the pharmaceutical composition comprises between about1 mg and about 4 mg of the crystalline composition according to FormulaI. In some embodiments, the pharmaceutical composition comprises betweenabout 1 mg and about 3 mg of the crystalline composition according toFormula I. In some embodiments, the pharmaceutical composition comprisesbetween about 1 mg and about 2 mg of the crystalline compositionaccording to Formula I.

In some embodiments, the pharmaceutical composition comprises betweenabout 500 mg of the crystalline composition according to Formula I. Insome embodiments, the pharmaceutical composition comprises between about450 mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 400mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 350mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 300mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 250mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 200mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 150mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 100mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 90mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 80mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 70mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 60mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 50mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 40mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 30mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 20mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 10mg of the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 5 mgof the crystalline composition according to Formula I. In someembodiments, the pharmaceutical composition comprises between about 1 mgof the crystalline composition according to Formula I.

Particle Size

In some embodiments, the pharmaceutical composition comprises thecrystalline composition according to Formula I in the form ofmicroparticles. In some embodiments, microparticles of the crystallinecomposition according to Formula I have an average size from about 1 μmto about 100 μm. In some embodiments, microparticles of the crystallinecomposition have an average size from about 1 μm to about 90 μm. In someembodiments, microparticles of the crystalline composition have anaverage size from about 1 μm to about 80 μm. In some embodiments,microparticles of the crystalline composition have an average size fromabout 1 μm to about 70 μm. In some embodiments, microparticles of thecrystalline composition have an average size from about 1 μm to about 60μm. In some embodiments, microparticles of the crystalline compositionhave an average size from about 1 μm to about 50 μm. In someembodiments, microparticles of the crystalline composition have anaverage size from about 1 μm to about 40 μm. In some embodiments,microparticles of the crystalline composition have an average size fromabout 1 μm to about 30 μm. In some embodiments, microparticles of thecrystalline composition have an average size from about 1 μm to about 20μm. In some embodiments, microparticles of the crystalline compositionhave an average size from about 1 μm to about 10 μm. In someembodiments, microparticles of the crystalline composition have anaverage size from about 1 μm to about 5 μm. In some embodiments,microparticles of the crystalline composition have an average size fromabout 100 μm. In some embodiments, microparticles of the crystallinecomposition have an average size from about 90 μm. In some embodiments,microparticles of the crystalline composition have an average size fromabout 80 μm. In some embodiments, microparticles of the crystallinecomposition have an average size from about 70 μm. In some embodiments,microparticles of the crystalline composition have an average size fromabout 60 μm. In some embodiments, microparticles of the crystallinecomposition have an average size from about 50 μm. In some embodiments,microparticles of the crystalline composition have an average size fromabout 40 μm. In some embodiments, microparticles of the crystallinecomposition have an average size from about 30 μm. In some embodiments,microparticles of the crystalline composition have an average size fromabout 20 μm. In some embodiments, microparticles of the crystallinecomposition have an average size from about 10 μm. In some embodiments,microparticles of the crystalline composition have an average size fromabout 9 μm. In some embodiments, microparticles of the crystallinecomposition have an average size from about 8 μm. In some embodiments,microparticles of the crystalline composition have an average size fromabout 7 μm. In some embodiments, microparticles of the crystallinecomposition have an average size from about 6 μm. In some embodiments,microparticles of the crystalline composition have an average size fromabout 5 μm. In some embodiments, microparticles of the crystallinecomposition have an average size from about 4 μm. In some embodiments,microparticles of the crystalline composition have an average size fromabout 3 μm. In some embodiments, microparticles of the crystallinecomposition have an average size from about 2 μm. In some embodiments,microparticles of the crystalline composition have an average size fromabout 1 μm. In some embodiments, microparticles of the crystallinecomposition have an average size less than about 100 μm. In someembodiments, microparticles of the crystalline composition have anaverage size less than about 90 μm. In some embodiments, microparticlesof the crystalline composition have an average size less than about 80μm. In some embodiments, microparticles of the crystalline compositionhave an average size less than about 70 μm. In some embodiments,microparticles of the crystalline composition have an average size lessthan about 60 μm. In some embodiments, microparticles of the crystallinecomposition have an average size less than about 50 μm. In someembodiments, microparticles of the crystalline composition have anaverage size less than about 40 μm. In some embodiments, microparticlesof the crystalline composition have an average size less than about 30μm. In some embodiments, microparticles of the crystalline compositionhave an average size less than about 20 μm. In some embodiments,microparticles of the crystalline composition have an average size lessthan about 10 μm. In some embodiments, microparticles of the crystallinecomposition have an average size less than about 5 μm.

In some embodiments, the pharmaceutical composition comprising thecrystalline composition according to Formula I, wherein the crystallinecomposition has a D90 from about 1 μm to about 50 μm. In someembodiments, the crystalline composition has a D90 from about 1 μm toabout 20 μm, from about 2 μm to about 19 μm, from about 3 μm to about 18μm, from about 4 μm to about 17 μm, from about 5 μm to about 16 μm, fromabout 6 μm to about 15 μm, from about 7 μm to about 14 μm, from about 8μm to about 13 μm, from about 9 μm to about 13 μm, or from about 8 μm toabout 12 μm. In some embodiments, the pharmaceutical compositioncomprising the crystalline composition according to Formula I, whereinthe crystalline composition has a D90 of more than about 1 μm, more thanabout 2 μm, more than about 3 μm, more than about 4μ, more than about 5μm, more than about 6 μm, more than about 7 μm, more than about 8 μm,more than about 9 μm, more than about 10 μm, more than about 11 μm, morethan about 12 μm, more than about 13 μm, more than about 14 μm more thanabout 15 μm more than about 16 μm, more than about 17 μm, more thanabout 18 μm, or more than about 19 μm. In some embodiments, thecrystalline composition has a D90 of less than about 20 μm, less thanabout 19 μm, less than about 18 μm, less than about 17 μm, less thanabout 16 μm, less than about 15 μm, less than about 14 μm, less thanabout 13 μm, less than about 12 μm, or less than about 11 μm.

Methods of Preparing the Crystalline Composition According to Formula I

Isolation and purification of the chemical entities and intermediatesdescribed herein can be performed, if desired, by any suitableseparation or purification procedure such as, for example, filtration,extraction, crystallization, column chromatography, thin-layerchromatography or thick-layer chromatography, or a combination of theseprocedures. Specific illustrations of suitable separation and isolationprocedures can be had by reference to the examples below. However, otherequivalent separation or isolation procedures can also be used. Prior tocrystallization, Compound 1 may be isolated in about 50% chemicalpurity, 55% chemical purity, 60% chemical purity, 65% chemical purity,70% chemical purity, 75% chemical purity, 80% chemical purity, 90%chemical purity, 91% chemical purity, 92% purity, 93% chemical purity,94% chemical purity, 95% chemical purity, 96% chemical purity, 97%chemical purity, 98% chemical purity, 99% chemical purity, about 98%chemical purity, or about 100% chemical purity.

In some embodiments, the crystalline composition according to Formula Idisclosed herein are obtained by crystallizing Compound 1 with achemical purity of less than about 98%, less than about 97%, less thanabout 96%, less than about 95%, less than about 94%, less than about93%, less than about 92%, less than about 91%, less than about 90%, lessthan about 89%, less than about 88%, less than about 87%, less thanabout 86%, less than about 85%, less than about 84%, less than about83%, less than about 82%, less than about 81%, less than about 80%, lessthan about 78%, less than about 76%, less than about 74%, less thanabout 72%, or less than about 70%. In some embodiments, the crystallinecomposition according to Formula I is obtained by crystallizing Compound1 with a chemical purity in the range of about 70% to about 99%, 80% toabout 96%, about 85% to about 96%, about 90% to about 96%, about 80% to98%, about 85% to about 98%, about 90% to about 98%, about 92% to about98%, about 94% to 98%, or about 96% to about 98%.

Preparation of Crystalline Form I

In one aspect, the present disclosure provides a method of preparing acrystalline composition according to Formula I, wherein the methodcomprises:

-   -   (a) dissolving        4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholine        (Compound 1) and oxalic acid in a solvent;    -   (b) heating the solution or slurry from step (a); and    -   (c) crystallizing the solution or slurry obtained in step (b) to        obtain the crystalline composition according to Formula I.

In some embodiments, the solvent in step (a) comprises acetone, heptane,water, 2-butanol, ethyl acetate, 2-propanol, methyl tert-butyl ether,ethanol, methyl ethyl ketone, 1-pentanol, or a combination thereof. Insome embodiments, the solvent in step (a) is heptane. In someembodiments, the solvent in step (a) is methyl tert-butyl ether ormethyl ethyl ketone. In some embodiments, the solvent in step (a) is amixture of heptane and methyl ethyl ketone.

In some embodiments, step (b) is heated at about 50° C.

In some embodiments, the concentration of the solution comprisingCompound 1 obtained in step (a) is between about 20 mg/mL and about 300mg/mL. In some embodiments, the concentration of the solution comprisingCompound 1 obtained in step (a) is between about 40 mg/mL and about 250mg/mL. In some embodiments, the concentration of the solution comprisingCompound 1 obtained in step (a) is between about 100 mg/mL and about 200mg/mL. In some embodiments, the concentration of the solution comprisingCompound 1 obtained in step (a) is between 125 mg/mL and about 175mg/mL.

In various embodiments, the method of preparing the crystallinecomposition according to Formula I involves recrystallization ofCompound 1 from a binary, tertiary, or greater solvent system,collectively understood as a multi-solvent system. In some embodiments,the method of preparing the crystalline composition according to FormulaI involves crystallization from a mono- or multi-solvent system, wherethe crystallization involves dissolving Compound 1 in the mono- ormulti-solvent system at a temperature above ambient temperature. In someembodiments, the dissolving of Compound 1 in the mono- or multi-solventsystem is performed at a temperature of about 0-90° C., 5-90° C., 10-90°C., 15-90° C., 20-90° C., 25-90° C., 30-90° C., 35-90° C., 40-90° C.,45-90° C., 50-90° C., 55-90° C., 60-90° C., 65-90° C., 70-90° C., 75-90°C., 80-90° C., 85-90° C., 0-80° C., 5-80° C., 10-80° C., 20-80° C.,30-80° C., 40-80° C., 50-80° C., 60-80° C., 70-80° C., 0-70° C., 5-70°C., 10-70° C., 15-70° C., 20-70° C., 30-70° C., 40-70° C., 50-70° C.,60-70° C., 0-60° C., 10-60° C., 20-60° C., 30-60° C., 40-60° C., or50-60° C.

In various embodiments, the crystallization further involves activelyheating the solution containing the dissolved Compound 1, for example toa temperature of about 25-100° C., 25-90° C., 25-80° C., 25-70° C.,25-60° C., 25-55° C., 25-50° C., 25-45° C., 25-40° C., 40-100° C.,40-90° C., 40-80° C., 40-70° C., 40-60° C., 40-50° C., 50-100° C.,50-90° C., 50-80° C., 50-70° C., 50-60° C., 60-100° C., 60-90° C.,60-80° C., 60-70° C., 70-100° C., 70-90° C., 70-80° C., 80-100° C., or80-90° C. In various embodiments, the solution containing the dissolvedCompound 1 is maintained at the heated temperature for a period of time,for example for about 30 min, about 1 h, about 2 h, about 3 h, about 4h, about 5 h, about 6 h, about 7 h, about 8 h, about 9 h, about 10 h,about 11 h, about 12 h, about 13 h, about 14 h, about 15 h, about 16 h,about 17 h, about 18 h, about 19 h, about 20 h, about 21 h, about 22 h,about 23 h, about 24 h or more.

In various embodiments, the crystallization further involves activelycooling the heated solution containing the dissolved Compound 1, forexample to a temperature of about 0-40° C., 0-30° C., 0-20° C., 0-10°C., 10-40° C., 10-30° C., 10-20° C., 20-40° C., 20-30° C., 20-10° C., or30° C.-40° C. In some embodiments, the crystallization further involvesactively cooling the heated solution containing the dissolved Compound 1to a temperature of about 20-30° C. In various embodiments, the solutioncontaining the dissolved Compound 1 is further maintained at this lowertemperature for a time period, for example for about 30 min, about 1 h,about 2 h, about 3 h, about 4 h, about 5 h, about 6 h, about 7 h, about8 h, about 9 h, about 10 h, about 11 h, about 12 h, about 13 h, about 14h, about 15 h, about 16 h, about 17 h, about 18 h, about 19 h, about 20h, about 21 h, about 22 h, about 23 h, about 24 h or more.

In various embodiments, the steps of active heating followed by activecooling are repeated multiple times, for example at least 2, at least 3,at least 4, at least 5, at least 6, at least 7, at least 8, at least 9,or at least 10 times. In some embodiments, the steps of active heatingfollowed by active cooling are repeated 2, 3, 4, 5, 6, 7, 8, 9, or 10times.

In various embodiments, the crystallization further involves filteringthe solution containing the obtained crystals of the crystallinecomposition according to Formula I. In some embodiments, thecrystallization optionally involves washing the obtained crystals by asolvent, for example by the recrystallization solvent one or more times.In some embodiments, the crystallization optionally involves drying theobtained crystals, for example under vacuum.

In some embodiments, the chemical purity of the crystalline compositionaccording to Formula I is greater than 60%, 70%, 80%, 90%, 95%, or 99%.In some embodiments, the chemical purity of the crystalline compositionaccording to Formula I is greater than about 90%. In some embodiments,the chemical purity of the crystalline composition according to FormulaI is greater than about 95%. In some embodiments, the chemical purity ofthe crystalline composition according to Formula I is greater than about99%. The chemical purity of the crystalline composition according toFormula I may be measured by any available analytical technique, forexample by HPLC analysis.

In various embodiments, the crystalline composition according to FormulaI is dry. In various embodiments, the crystalline composition accordingto Formula I is non-solvated. In various embodiments, the crystallinecomposition according to Formula I is non-hydrated. In variousembodiments, the crystalline composition according to Formula I isanhydrous.

Methods of Treatment

In one aspect, the present disclosure provides a method of treating,preventing, or improving the symptoms of a disease or disorder in asubject in need thereof, comprising administering to the subject acrystalline composition according to Formula I as described herein, or apharmaceutical composition comprising the crystalline compositionaccording to Formula I as described herein.

In another aspect, the present disclosure provides a method of treatingor preventing testicular adrenal rest tumors (TART) or ovarian adrenalrest tumors (OART) in a subject in need thereof, comprisingadministering to the subject a crystalline composition according toFormula I as described herein, or a pharmaceutical compositioncomprising the crystalline composition according to Formula I asdescribed herein. In some embodiments, the subject has congenitaladrenal hyperplasia (CAH).

In another aspect, the present disclosure provides a method of treatingcongenital adrenal hyperplasia (CAH) in a subject in need thereof,comprising administering to the subject a crystalline compositionaccording to Formula I as described herein, or a pharmaceuticalcomposition comprising a crystalline composition according to Formula Ias described herein. In some embodiments, the CAH is classic CAH. Insome embodiments, the CAH is non-classical CAH.

In another aspect, the present disclosure provides a method of improvinghyperandrogenic symptoms in a subject in need thereof, comprisingadministering to the subject a crystalline composition according toFormula I as described herein, or a pharmaceutical compositioncomprising the crystalline composition according to Formula I asdescribed herein. In some embodiments, the hyperandrongic symptoms areselected from the group consisting of acne, hirsutism, and alopecia.

In another aspect, the present disclosure provides a method of treatingmenstrual irregularity, ovulatory dysfunction or infertility, in asubject in need thereof, comprising administering to the subject acrystalline composition according to Formula I as described herein, or apharmaceutical composition comprising the crystalline compositionaccording to Formula I as described herein.

In another aspect, the present disclosure provides a method of improvingmetabolic symptoms in a subject in need thereof, comprisingadministering to the subject a crystalline composition according toFormula I as described herein, or the pharmaceutical compositioncomprising the crystalline composition according to Formula I asdescribed herein. In some embodiments, the metabolic symptoms areselected from the group consisting of body weight, BMI, fat mass, waistcircumference, blood pressure and glycemic control.

In another aspect, the present disclosure provides a method of treatingpolycystic ovary syndrome with functional ovarian hyperandrogenism andfunctional adrenal hyperandrogenism (PCOS−FOH+FAH) in a subject in needthereof, comprising administering to the subject a crystallinecomposition according to Formula I as described herein, or thepharmaceutical composition comprising the crystalline compositionaccording to Formula I as described herein.

In another aspect, the present disclosure provides a method of treatingpolycystic ovary syndrome with functional adrenal hyperandrogenism(PCOS-FAH) in a subject in need thereof, comprising administering to thesubject a crystalline composition according to Formula I as describedherein, or the pharmaceutical composition comprising the crystallinecomposition according to Formula I as described herein.

In another aspect, the present disclosure provides a method of treatingendometriosis or improving the symptoms of endometriosis in a subject inneed thereof, comprising administering to the subject a crystallinecomposition according to Formula I as described herein, or thepharmaceutical composition comprising the crystalline compositionaccording to Formula I as described herein. In some embodiments, theadministration of the crystalline composition or the pharmaceuticalcomposition improves the symptom of pain experienced by the subject. Insome embodiments, the administration of the crystalline composition orthe pharmaceutical composition reduces the symptoms of pain experiencedby the subject. In some embodiments, the administration of thecrystalline composition or the pharmaceutical composition prevents thesymptom of pain experienced by the subject. In some embodiments, theadministration of the crystalline composition or the pharmaceuticalcomposition eliminates the symptom of pain experienced by the subject.

In some embodiments, the methods described herein result in thereduction of a hormone level. Such hormones include deoxycorticosterone,11-deoxycortisol, Cortisol, corticosterone, aldosterone, pregnenolone,hydroxy pregnenolone, progesterone, 17a-hydroxy progesterone (17-OHP),dehydroepiandrosterone, androstenediol, androstenedione, testosterone,dihydrotestosterone, estrone, estradiol, estriol, andadrenocorticotropic hormone (ACTH). In some embodiments, the methodsdescribed herein result in the reduction of 17a-hydroxy progesterone(17-OHP). In some embodiments, the methods described herein result inthe reduction of adrenocorticotropic hormone (ACTH), also known ascorticotropin.

In various embodiments of the methods as described herein, thecrystalline composition or the pharmaceutical composition isadministered at a dose from about 5 mg/day to about 1000 mg/day. In someembodiments, the crystalline composition or the pharmaceuticalcomposition is administered in a fed state. In some embodiments, thecrystalline composition or the pharmaceutical composition isadministered in a fasted state. In some embodiments, the crystallinecomposition or the pharmaceutical composition is administered at leastonce per day.

In some embodiments of the methods described herein, the crystallinecomposition or the pharmaceutical composition is administered atbedtime. In some embodiments, the methods described herein includeadministration of the crystalline composition or the pharmaceuticalcompositions described herein less than about 4 hours before sleep. Insome embodiments, the methods described herein include administration ofthe crystalline composition or the pharmaceutical compositions describedherein less than about 3 hours before sleep. In some embodiments, themethods described herein include administration of the crystallinecomposition or the pharmaceutical compositions described herein lessthan about 2 hours before sleep. In some embodiments, the methodsdescribed herein include administration of the crystalline compositionor the pharmaceutical compositions described herein less than about 1hour before sleep. In some embodiments, the methods described hereininclude administration of the crystalline composition or thepharmaceutical compositions described herein less than about 30 minsbefore sleep.

In some embodiments, the methods described herein include administrationof the crystalline composition or the pharmaceutical compositionsdescribed herein at or before the expected circadian release ofadrenocorticotropic hormone (ACTH). In some embodiments, the methodsdescribed herein include administration of the crystalline compositionor the pharmaceutical compositions described herein about 3-4 hoursbefore the expected circadian release of adrenocorticotropic hormone(ACTH).

In various embodiments of the methods as described herein, the methodfurther comprises administering to the subject an additionalchemotherapeutic agent. In some embodiments, the additionalchemotherapeutic agent is glucocorticoid, a mineralocorticoid, an ACAT1inhibitor, or an anti-androgen agent. In some embodiments, theglucocorticoid is beclomethasone, betamethasone, budesonide, cortisone,dexamethasone, hydrocortisone, methylprednisolone, prednisolone,prednisone, or triamcinolone. In some embodiments, the mineralocorticoidis fludrocortisone. In some embodiments, the additional chemotherapeuticagent is another CRF1antagonist.

In various embodiments of the methods as described herein, the methodfurther comprises an additional treatment selected from surgicalresection of the tumors and radiation therapy, or a combination thereof.In some embodiments, the additional therapy is surgical resection andthe surgical resection is prior to, after, and/or concurrent withadministration of the crystalline composition as described herein, orthe pharmaceutical composition comprising the crystalline composition asdescribed herein. In some embodiments, the additional therapy isradiation therapy and the radiation therapy is prior to, after, and/orconcurrent with administration of the crystalline composition asdescribed herein, or the pharmaceutical composition comprising thecrystalline composition as described herein.

In various embodiments of the methods, the subject is from about 9 yearsof age to about 18 years of age. In some embodiments, the subject isfrom about 8 years of age to about 55 years of age.

EXAMPLES

The following examples serve to further describe the manner of using thepresent disclosure. These examples are presented for illustrativepurpose and should not serve to limit the true scope of the presentdisclosure.

In carrying out the procedures of the methods described herein, it is ofcourse to be understood that references to particular buffers, media,reagents, cells, culture conditions, and the like are not intended to belimiting, but are to be read so as to include all related materials thatone of ordinary skill in the art would recognize as being of interest orvalue in the particular context in which that discussion is presented.For example, it is often possible to substitute on buffer system orculture medium for another and still achieve similar, if not identical,results. Those of skill in the art will have sufficient knowledge ofsuch systems and methodologies so as to able, without undueexperimentation, to make such substitutions as will optimally servetheir purposes in using the methods and procedures disclosed herein.

Example 1—Preparation and Characterization of the CrystallineComposition According to Formula I Preparation of the CrystallineComposition according to Formula I

A mixture of 185.0 mg (0.441 mmol) of4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholine(Compound 1), 45.0 mg (0.500 mmol) of oxalic acid, and 2.5 mL ofdiisopropyl ether was agitated. After one hour, an additional 1 mL ofdiisopropyl ether was added. After stirring overnight, the mixture wasvacuum filtered and the resulting solid was dried to afford 170 mg(760%) of the crystalline composition according to Formula I as solid.

X-Ray Powder Diffraction

X-ray powder diffraction (XPRD) patterns were obtained on a RigakuSmart-Lab X-ray diffraction system. A CuK source (=0.71073 Å) operatingminimally at 40 kV and 44 mA scans each sample between 2 and 40 degrees2θ. The step size is 0.02820.

The XRPD pattern obtained for the crystalline composition according toFormula I is summarized in Table 1 below and shown in FIG. 1 .

TABLE 1 XRPD Data of the Crystalline Composition according to Formula IPeak # Angle (°2-θ) Intensity (%) 1 5.44 31 2 8.82 12 3 10.84 100 411.70 12 5 14.60 8 6 15.56 6 7 15.96 52 8 16.28 5 9 16.70 10 10 17.66 411 18.44 5 12 18.82 6 13 19.18 8 14 19.60 2 15 20.02 11 16 20.50 11 1720.78 20 18 21.72 7 19 22.12 2 20 22.74 18 21 23.04 16 22 23.44 31 2324.80 48 24 25.52 6 25 25.92 9 26 26.58 4 27 26.80 14 28 26.94 8 2927.62 3 30 28.00 13 31 28.86 14 32 29.54 3 33 31.26 3 34 31.66 5 3531.88 4 36 32.16 3 37 32.48 2 38 32.86 5 39 33.46 2 40 34.36 2 41 35.023 42 35.44 1 43 35.98 2 44 36.72 4 45 37.04 3 46 37.80 5 47 38.28 2 4838.90 2 49 39.20 2

Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry analysis was carried out on a TAInstruments Q2500 Discovery Series instrument. The instrumenttemperature calibration was performed using indium. The DSC cell waskept under a nitrogen purge of about 50 mL per minute during eachanalysis. The sample was placed in a standard, crimpled, aluminum panand was heated from approximately 25° C. to 350° C. at a rate of 10° C.per minute. The DSC trace of the crystalline composition according toFormula I is shown in FIG. 2 .

Thermogravimetric Analysis (TGA)

Thermogravimetry analyses were carried out using a TA InstrumentsDiscovery TGA 5500 instrument that was cooled using a TA InstrumentsRefrigerated Cooling System (RCS) 90 chiller. The instrument balance wascalibrated using class M weights and temperature calibration wasperformed by measurement of the Curie point of Alumel®. Sample wasloaded onto a platinum sample pan and the pan was loaded into the TGinstrument. The pan was heated from ambient temperature to 350° C. at arate of 10° C. per minute. The instrument was controlled using TA Triossoftware. The TGA trace of the crystalline composition according toFormula I is shown in FIG. 3 .

Dynamic Vapor Sorption (DVS)

The DVS analysis was carried out on a TA Instruments Q5000 sorptionanalyzer. The instrument was calibrated with standard weights and asodium bromide standard for humidity. For each analysis, a portion ofthe sample was weighed into a metal-coated, quartz pan. Each sample wasanalyzed at 25° C. with a maximum equilibration time of 60 minutes in10% relative humidity (RH) steps from 5 to 95% RH (adsorption cycle) andfrom 95 to 5% RH (desorption cycle). Data collection was performed usingAdvantage for Q Series version 5.5.23. The percent weight change valueswere calculated using Microsoft Excel®. The DVS trace of the crystallinecomposition according to Formula I is shown in FIG. 4 .

Infrared (IR)

The IR spectrum was obtained using a Nicolet iS50 Model 60825Fourier-transform (FT) IR spectrophotometer equipped with a deuteratedtriglycine sulfate (DTGS) detector, a potassium bromide (KBr)beamsplitter, and an electronically temperature controlled (ETC)Ever-Glo® IR source. The instrument was configured with a SMART iTRdiamond attenuated total reflectance (ATR) sampling accessory. Thesingle beam scan of the background (air) and sample were collected with128 signal-averaged scans at a resolution of 2 cm-1 over the spectralrange 400-4000 cm-1. The wavelength calibration was verified using acertified polystyrene standard. Data collection and processing wasperformed using Omnic 9.2 software. The IR spectrum of the crystallinecomposition according to Formula I is shown in FIG. 5 .

Proton Nuclear Magnetic Resonance (¹H NMR)

The 1H NMR spectrum was acquired on a Bruker Avance 400 MHz spectrometerusing TopSpin v3.2 software. The sample was dissolved in CD3OD and theresulting solution was transferred into a 5-mm NMR tube for subsequentdata acquisition. Data collection parameters are shown in Table 14. Thespectrum was processed using the program MNova and referenced to thechemical shift of the residual protons in CD30D (3.31 ppm). The ¹H NMRspectrum of the crystalline composition according to Formula I is shownin FIG. 6 .

Raman

The Raman spectrum was acquired utilizing a Thermo Scientific model iS50Fourier-transform (FT) IR spectrophotometer equipped with a Ramanaccessory. The system is equipped with an indium gallium arsenide(InGaAs) detector, a calcium fluoride (CaF2) beamsplitter, and a 2.5 Wlaser operating at 1064 nm. The module was conFIG.d with a 180°reflective sampling accessory. A sample was prepared by loadingparticles onto a glass slide. Each FT-Raman spectrum was collected using0.50 W laser power with 256 signal-averaged scans at a resolution of 4cm-1 over the spectral range 100-3700 cm-1. The wavelength calibrationwas verified using a polystyrene. Data acquisition and processing wereperformed using Omnic 9.7 software. The Raman spectrum of thecrystalline composition according to Formula I is shown in FIG. 7 .

1-30. (canceled)
 31. A method of treating, preventing, or improving thesymptoms of a disease or disorder in a subject in need thereof,comprising administering to the subject a crystalline compositioncomprising Compound 1:

wherein said crystalline composition is characterized by: a) an X-raydiffraction pattern comprising peaks at 10.84±0.2° 2-θ, 15.96 0.2° 2-θ,23.44±0.2° 2-θ, or 24.80±0.2° 2-θ, as measured by X-ray powderdiffraction using an X-ray wavelength of 0.71073 Å; b) a differentialscanning calorimetry (DSC) thermogram comprising an endotherm in therange of about 160° C. to 170° C.; c) a differential scanningcalorimetry (DSC) thermogram comprising an endotherm with an onset ofabout 164° C. and a peak of about 166° C.; d) a thermogravimetricanalysis (TGA) thermogram comprising a loss in mass of about 11% over atemperature range of about 25° C. to about 200° C.; or e) combinationsthereof.
 32. The method of claim 31, wherein the crystalline compositionis characterized by the X-ray diffraction pattern comprising peaks at10.84±0.2° 2-θ, 15.96±0.2° 2-θ, 23.44±0.2° 2-θ, or 24.80 0.2° 2-θ, asmeasured by X-ray powder diffraction using an X-ray wavelength of0.71073 Å.
 33. The method of claim 32, wherein the X-ray powderdiffraction pattern comprises peaks at 10.84±0.2° 2-θ, 15.96±0.2° 2-θ,23.44±0.2° 2-θ, and 24.80±0.2° 2-0.
 34. The method of claim 32, whereinthe X-ray powder diffraction pattern further comprising at least onepeak selected from 5.44±0.2° 2-θ, 20.78±0.2° 2-θ, 22.74±0.2° 2-θ,23.04±0.2° 2-θ, 26.80±0.2° 2-θ, and 28.86±0.2° 2-0.
 35. The method ofclaim 32, wherein the X-ray powder diffraction pattern furthercomprising at least five peaks selected from 8.82±0.2° 2-θ, 11.70±0.2°2-θ, 14.60±0.2° 2-θ, 15.56±0.2° 2-θ, 16.70±0.2° 2-θ, 18.82±0.2° 2-θ,19.18±0.2° 2-θ, 20.02±0.2° 2-θ, 20.50±0.2° 2-θ, 21.72±0.2° 2-θ,25.52±0.2° 2-θ, 25.92±0.2° 2-θ, 26.94±0.2° 2-θ, and 28.00 0.2° 2-θ. 36.The method of claim 31, wherein the crystalline composition ischaracterized by a differential scanning calorimetry (DSC) thermogramcomprising an endotherm in the range of about 160° C. to 170° C.
 37. Themethod of claim 31, wherein the crystalline composition is characterizedby a differential scanning calorimetry (DSC) thermogram comprising anendotherm with an onset of about 164° C. and a peak of about 166° C. 38.The method of claim 37, wherein the crystalline composition ischaracterized by a melting point of about 166° C.
 39. The method ofclaim 31, wherein the crystalline composition is characterized by athermogravimetric analysis (TGA) thermogram comprising a loss in mass ofabout 11% over a temperature range of about 25° C. to about 200° C. 40.The method of claim 31, wherein the disease or disorder is polycysticovary syndrome (PCOS).
 41. The method of claim 40, wherein the PCOS isPCOS with functional ovarian hyperandrogenism and functional adrenalhyperandrogenism (PCOS−FOH+FAH).
 42. The method of claim 40, wherein thePCOS is PCOS with functional adrenal hyperandrogenism (PCOS+FAH). 43.The method of claim 31, wherein the disease or disorder is congenitaladrenal hyperplasia (CAH).
 44. The method of claim 43, wherein the CAHis classic CAH.
 45. The method of claim 43, wherein the CAH isnon-classical CAH.
 46. The method of claim 31, wherein the disease ordisorder is testicular adrenal rest tumors (TART) or ovarian adrenalrest tumors (OART).
 47. The method of claim 31, wherein the disease ordisorder is endometriosis.
 48. The method of claim 31, wherein themethod further comprises administering to the subject a glucocorticoid.49. The method of claim 48, wherein the glucocorticoid isbeclomethasone, betamethasone, budesonide, cortisone, dexamethasone,hydrocortisone, methylprednisolone, prednisolone, prednisone, ortriamcinolone.